Bostick Brian, Habibi Javad, DeMarco Vincent G, Jia Guanghong, Domeier Timothy L, Lambert Michelle D, Aroor Annayya R, Nistala Ravi, Bender Shawn B, Garro Mona, Hayden Melvin R, Ma Lixin, Manrique Camila, Sowers James R
Division of Cardiovascular Medicine, Department of Medicine, University of Missouri, Columbia, Missouri;
Division of Endocrinology, Diabetes and Metabolism, University of Missouri, Columbia, Missouri; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri; and.
Am J Physiol Heart Circ Physiol. 2015 May 1;308(9):H1126-35. doi: 10.1152/ajpheart.00898.2014. Epub 2015 Mar 6.
Overnutrition/obesity predisposes individuals, particularly women, to diastolic dysfunction (DD), an independent predictor of future cardiovascular disease. We examined whether low-dose spironolactone (Sp) prevents DD associated with consumption of a Western Diet (WD) high in fat, fructose, and sucrose. Female C57BL6J mice were fed a WD with or without Sp (1 mg·kg(-1)·day(-1)). After 4 mo on the WD, mice exhibited increased body weight and visceral fat, but similar blood pressures, compared with control diet-fed mice. Sp prevented the development of WD-induced DD, as indicated by decreased isovolumic relaxation time and an improvement in myocardial performance (<Tei index) and septal annular velocity (<E'-to-A' ratio), as assessed by echocardiography, as well as decreased diastolic relaxation time/increased diastolic initial filling rate, as assessed by MRI. The relationship between passive sarcomere length of cardiac myocytes and ventricular pressure was monitored using di-8-ANEPPS staining of the t-tubule network in hearts ex vivo. Sp administration led to longer sarcomere lengths at each pressure indicative of improved ventricular compliance in WD-fed mice. Sp also prevented left ventricular hypertrophy, interstitial fibrosis, and oxidative stress. Sp prevented the WD-induced increased expression of myocardial proinflammatory M1 macrophage markers monocyte chemoattractant protein-1 and CD11c and increased the expression of the anti-inflammatory M2 macrophage marker CD206. These findings demonstrate that WD-induced DD is associated with increased oxidant stress, fibrosis, and immune dysregulation. Mineralocorticoid receptor antagonism enhanced M2 macrophage polarization and ameliorated oxidant stress and fibrosis. This work supports a novel blood pressure-independent effect of MR antagonism as a strategy to prevent diet-induced DD in women. Mineralocorticoid antagonism; low-dose spironolactone; aldosterone;high-fat diet; high-fructose diet; oxidative stress; inflammation; cardiac hypertrophy; myocardial compliance.
营养过剩/肥胖使个体，尤其是女性，易患舒张功能障碍（DD），这是未来心血管疾病的一个独立预测指标。我们研究了低剂量螺内酯（Sp）是否能预防与高脂肪、果糖和蔗糖的西方饮食（WD）相关的舒张功能障碍。给雌性C57BL6J小鼠喂食含或不含Sp（1毫克·千克⁻¹·天⁻¹）的西方饮食。在喂食西方饮食4个月后，与喂食对照饮食的小鼠相比，小鼠体重和内脏脂肪增加，但血压相似。通过超声心动图评估，Sp可预防西方饮食诱导的舒张功能障碍，表现为等容舒张时间缩短、心肌性能改善（<Tei指数）和室间隔环速度改善（<E'与A'比值），通过磁共振成像评估，舒张时间缩短/舒张初始充盈率增加。使用离体心脏中T小管网络的di-8-ANEPPS染色监测心肌细胞被动肌节长度与心室压力之间的关系。Sp给药导致在每个压力下肌节长度更长，表明喂食西方饮食的小鼠心室顺应性得到改善。Sp还可预防左心室肥厚、间质纤维化和氧化应激。Sp可预防西方饮食诱导的心肌促炎M1巨噬细胞标志物单核细胞趋化蛋白-1和CD11c表达增加，并增加抗炎M2巨噬细胞标志物CD206的表达。这些发现表明，西方饮食诱导的舒张功能障碍与氧化应激增加、纤维化和免疫失调有关。盐皮质激素受体拮抗增强了M2巨噬细胞极化，减轻了氧化应激和纤维化。这项工作支持了盐皮质激素受体拮抗作为一种预防女性饮食诱导的舒张功能障碍的策略具有一种新的不依赖血压的作用。盐皮质激素拮抗；低剂量螺内酯；醛固酮；高脂肪饮食；高果糖饮食；氧化应激；炎症；心脏肥大；心肌顺应性。
